The Pharmacological Characterization of Hco-UNC-49, a GABA-gated Chloride Channel from the Parasitic Nematode Haemonchus contortus

Abstract

Compared to mammals, nematodes appear to exhibit a unique GABAergic nervous system. Haemonchus controtus is a parasitic nematode that infects ruminants worldwide. Hco-UNC-49 is a H. contortus GABA-gated chloride channel and is an orthologue to the UNC-49 channel from the free-living nematode Caenorhabditis elegans. Previous research by our group has shown that while the UNC-49 channels from the two nematodes share similar sequence homology they do not share identical sensitivity to GABA. To further investigate the characteristics of the Hco-UNC-49 channel, this study tested the effects of various modulators, insecticides and anti-parasitic drugs on channel function. Most notably, the molecules penicillin G, propofol and pregnenolone sulfate all had similar effects on Hco-UNC-49 as reported previously for Cel-UNC-49. On the other hand, Hco-UNC-49 appears to be less sensitive to picrotoxin inhibition compared to what has been reported for Cel-UNC-49. Novel effects of a number of anthelmintics were also observed. For example, the anthelmintics ivermectin and moxidectin both enhanced Hco-UNC-49 GABA responses, while piperazine was able to directly activate Hco-UNC-49 at high concentrations. These results suggest that Hco-UNC-49 is likely an in vivo target for these anthelmintics.